The general inflammatory response of humans occurs whenever tissue is injured. The injury may be due to a wide variety of conditions including infection by bacteria, viruses or fungi, invasion by cancer cells, allergic or autoimmune diseases and physically- or chemically-induced trauma. In all of these diseases and conditions the complement system is activated resulting in production of C5a which serves to amplify and exacerbate the resulting inflammation. By binding to and blocking the C5a receptor, the peptides of the present invention can reduce or prevent C5a-mediated inflammation. In addition, these peptides may inhibit the immunoregulatory effects of C5a and thus indirectly cause immunoregulation.
The anaphylatoxin C5a is one of the more potent biologic factors known to man. This factor is generated when C5 is cleaved at a specific site by convertases (proteolytic enzymes) of the blood complement system, as well as by enzymes of the coagulation system. C5a is the last in a series of three anaphylatoxins that are released during activation of the complement cascade. Anaphylatoxins C3a and C4a, factors released prior to C5a in the activation sequence, are considerably less potent than C5a for inducing cellular histamine release and tissue spasmogenic responses, and for enhancing vascular permeability. Furthermore, C5a is the most active leukotactic factor known to originate from any blood component.
Upon release, C5a binds to its specific cellular receptors present on blood leukocytes including polymorphonuclear neutrophils, monocytes, basophils, and eosinophils, and to tissue-resident cells such as macrophages and mast cells. Such binding of C5a to its receptor triggers cells to release vasoactive and inflammatory substances including histamine, leukotrienes, prostaglandins, and proteolytic enzymes. These and other substances produce contraction of smooth muscle, platelet aggregation, vasodialation, and increased vascular permeability which results in the pain and swelling which is characteristic of inflammation. In addition, C5a is a powerful attractant of leukocytes to sites of inflammation by the process of chemotaxis which leads to an increased cellular inflammatory response. C5a also exerts immunomodulatory effects on immune responsiveness as evidenced by its ability to potentiate the primary antibody response to antigens in vitro.